Indirubin Derivatives: Synthesis, Physicochemical Profiling, Toxicity Assessment, and Molecular Docking Investigations Against EGFR and HIV Target Substrates

ABSTRACT Indirubin‐based alkaloids constitute an important chemotype with documented anticancer and antiviral potential. In this study, a concise cascade alkylation strategy was employed to generate a diverse library of indirubinoid derivatives from the parent indirubin scaffold using alkylating agents in the presence of cesium carbonate, affording the targeted molecules in good to excellent yields. Comprehensive in silico analyses were performed to evaluate physicochemical suitability, ADMET behavior, predicted metabolites, and TOX21 toxicity endpoints, collectively indicating that several derivatives meet key drug‐likeness and safety criteria. Molecular docking further highlighted them as good candidates for binding with the extracellular domain of EGFR (PDB: 1NQL), as compounds I16 (−8.06 kcal/mol), I18 (−8.83 kcal/mol), I21 (−8.09 kcal/mol), and I23 (−7.61 kcal/mol) demonstrated substantially stronger binding affinities than the reference gefitinib (−6.74 kcal/mol) during the simulation experiments. Similarly, against HIV‐II protease (PDB: 1HSG), derivatives I16 , I18 , I20 , and I21 exhibited more favorable predicted docking scores than lopinavir under the same computational protocol, with I18 showing the strongest calculated binding within this compound set. These synergistic synthetic and computational findings identify indirubinoids as strong candidates for future development of anticancer and anti‐HIV drug leads.